Cycloaliphatic prostaglandin analogues

ABSTRACT

Compounds of formula (I): ##STR1## wherein: m is 1 or 2; n is 4 to 8; X is CO, protected CO, or CROH wherein R is hydrogen or C 1-4  alkyl and wherein the OH moiety may be protected; R 1  is hydrogen or CO 2  R 1  represents an ester group in which the R 1  moiety contains from 1 to 12 carbon atoms; R 3  is hydroxy, or protected hydroxy; R 2  and R 4  are separately hydrogen, C 1-9  alkyl, C 5-8  cycloalkyl, C 5-8  cycloalkyl-C 1-6  alkyl, phenyl, phenyl C 1-6  alkyl, naphthyl, naphthyl C 1-6  alkyl, any of which phenyl or naphthyl moieties may be substituted by one or more halogen, trifluoromethyl, C 1-6  alkyl, C 1-6  alkoxy or nitro groups; or R 2  and R 4  taken with the carbon atom to which they are joined represent a C 5-8  cycloalkyl group; and salts thereof; except that when one of R 2  and R 4  is hydrogen or C 1-4  alkyl then the other of R 2  and R 4  cannot be hydrogen or C 1-9  alkyl; have useful pharmacological properties including antigastric secretion, bronchodilator and platelet aggregration inhibition activities.

CROSS-REFERENCE

This is a division of Ser. No. 732,726 filed Oct. 15, 1976, now U.S.Pat. No. 4,138,407 issued Feb. 6, 1979.

This invention relates to novel compounds having pharmacologicalactivity, to a process for their preparation, to intermediates useful inthat process, and to pharmaceutical compositions containing them.

More specifically the invention relates to cyclic amides in which thenitrogen atom is substituted by an aliphatic or aliphatic-aromatic groupand one α-carbon atom is substituted by an aliphatic group.

Natural prostaglandins and analogues thereof are known to possess a widevariety of pharmacological activities.

Offenlegungsschrift No: 2323193 discloses that pyrazolidine derivativesof the formula (I)': ##STR2## wherein A is CH═CH or C.tbd.C; R is H, analkali metal, an amine salt, or an ≯12C hydrocarbon or chlorohydrocarbonresidue; m is 0 or 1; n is 0-6; p is 0-6; and Y and Z are O or H₂ exceptthat Y and Z are not both O; have similar biological properties to theprostaglandins or are antagonists of prostaglandins.

A paper by Bolliger and Muchowski (Tet. Letters, 1975, 2931) describesthe preparation of 11-desoxy-8-azaprostaglandin E₁, but states only thatone epimer thereof was more active in several biological assays then theother epimer.

Copending U.S. patent application No. 632975, now abandoned, disclosesthat compounds of the formula (I)": ##STR3## wherein: X is CO, protectedCO, CROH in which R is hydrogen or C₁₋₄ alkyl and in which the OH moietymay be protected;

Y is CH₂ CH₂ or CH═CH; Z is CO or CH₂ ; n is 1 to 8; m is 1, 2 or 3; R₁is hydrogen, CH₂ OH, CH₂ OH in which the OH moiety is protected, CO₂ Wwherein W is hydrogen or CO₂ W represents an ester group in which theester moiety contains from 1 to 12 carbon atoms, or CONH₂ ; R₂ ishydrogen, C₁₋₄ alkyl, or taken together with R₃ and the carbon atom towhich it is attached represents a carbonyl group; R₃ is hydrogen,hydroxy or protected hydroxy; R₄ is hydrogen or C₁₋₉ alkyl; and saltsthereof; have useful pharmacological activity. This subject matter wasfirst published in Belgium patent No. 835989 on the 26th May 1976, adate later than the filing dates of the two U.K. Applications Nos:43990/75 and 21278/76 from which priority has been claimed for thepresent invention.

A novel class of compounds having useful pharmacological activity hasnow been discovered, which compounds are structurally distinct from theprior art referred to above.

The present invention provides a compound of the formula (I): ##STR4##wherein: m is 1 or 2;

n is 4 to 8;

X is CO, protected CO, or CROH wherein R is hydrogen or C₁₋₄ alkyl andwherein the OH moiety may be protected; R₁ is hydrogen or CO₂ R₁represents an ester group in which the R₁ moiety contains from 1 to 12carbon atoms;

R₃ is hydroxy, or protected hydroxy;

R₂ and R₄ are separately hydrogen, C₁₋₉ alkyl, C₅₋₈ cycloalkyl, C₅₋₈cycloalkyl-C₁₋₆ alkyl, phenyl, phenyl C₁₋₆ alkyl, naphthyl, naphthylC₁₋₆ alkyl, any of which phenyl or naphthyl moieties may be substitutedby one or more halogen, trifluoromethyl, C₁₋₆ alkyl, C₁₋₆ alkoxy ornitro groups; or R₂ and R₄ taken with the carbon atom to which they arejoined represent a C₅₋₈ cycloalkyl group; and salts thereof; except thatwhen one of R₂ and R₄ is hydrogen or C₁₋₄ alkyl then the other of R₂ andR₄ cannot be hydrogen or C₁₋₉ alkyl.

Suitably m is 1 and n is 5, 6 or 7, preferably 6.

Suitable protected hydroxyl groups CROH and R₃ include readilyhydrolysable groups such as acylated hydroxy groups in which the acylmoiety contains 1 to 4 carbon atoms, for example the acetoxy group; andhydroxy groups etherified by readily removable inert groups such as thebenzyl or like groups. Preferably R₃ is hydroxy, and the hydroxy moietyin CROH is unprotected.

X may be a protected CO group. Suitable examples of such protected COgroups X include groups formed by conventional carbonyl addition andcondensation reactions such as ketals, thioketals, hemithioketals,oximes, semicarbazones, hydrazones and the like. Of such groups oftenthe ketal type derivatives will be most useful, for example when X is agroup ##STR5##

Examples of suitable groups X include CO, CHOH, C(CH₃)OH and C(C₂ H₅)OH.

Preferably X is CO, CHOH or C(CH₃)OH, most preferably CO.

R₁ is hydrogen or CO₂ R₁ represents an ester group in which the R₁moiety contains from 1 to 12 carbon atoms. Examples of R₁ includehydrogen, methyl, ethyl, propyl, butyl, phenyl, benzyl, toluyl, and thelike, while normally hydrogen or C₁₋₄ alkyl groups are preferred.

Suitable groups R₄ when R₄ is an alkyl group include C₄₋₉ alkyl groups.Such C₄₋₉ alkyl groups may be straight chain alkyl groups, such asn-butyl, n-pentyl, n-hexyl and n-heptyl, or may be alkyl groups branchedby one or two methyl groups (at the same or different carbon atoms).Thus for example R₄ may be a group CH₂ R₅, CH(CH₃)R₅ or C(CH₃)₂ R₅,wherein R₅ is a straight chain alkyl group such that the carbon contentof the resultant group R₄ is 4 to 9.

In general preferred groups R₄ when R₄ is an alkyl group includestraight chain pentyl, hexyl and heptyl groups. Of these, straight chainhexyl is often the most useful. Other preferred groups R₄ include groupsCH(CH₃)R₅ and C(CH₃)₂ R₅ wherein R₅ is straight chain butyl, pentyl andhexyl.

When R₄ is or contains a C₅₋₈ cycloalkyl moiety, the moiety is suitablya cyclohexyl moiety. Examples of suitable C₁₋₆ alkyl moieties when R₄ isa C₅₋₈ cycloalkyl-C₁₋₆ alkyl group include methyl, ethyl, propyl, butyland amyl.

Examples of suitable groups R₄ when R₄ is an aryl group as previouslydefined include phenyl, phenylmethyl, phenylethyl, phenyl n-propyl,phenyl n-butyl, naphthyl, naphthylmethyl, naphthylethyl, naphthyln-propyl, and naphthyl-n-butyl, and such groups branched in the alkylmoiety by one or two methyl groups (at the same or different carbonatoms). These groups may be substituted in the phenyl or naphthyl moietyby normally one, two or three groups selected from these substituentgroups listed herein before. Examples of suitable substituent groupsinclude fluorine, chlorine and bromine atoms and CF₃, methyl, ethyl, n-and iso-propyl, methoxy, ethoxy n-and iso-propoxy and nitro groups.Preferably the aryl moieties when substituted by such groups will bemono or di-substituted.

Particularly suitable values for R₂ are hydrogen, C₁₋₄ alkyl and phenyl,for example hydrogen, methyl, ethyl and phenyl. Of these groupspreferred groups include methyl and ethyl.

Otherwise R₂ can suitably represent groups such as those described aboveas suitable and preferred groups for R₄.

Also, R₂ and R₄ taken with the carbon atom to which they are joined canrepresent a C₅₋₈ cycloalkyl group, such as the cyclohexyl group.

The compounds of the formula (I) may form conventional acid salts whenR₁ is hydrogen. Such salts include those with alkali and alkaline earthmetals, suitably sodium and potassium, and ammonium and substitutedammonium salts.

A group of compounds within the compounds of the formula (I) as definedare those wherein X is CO, or CROH wherein R is hydrogen or C₁₋₄ alkyland wherein the OH moiety may be protected; R₂ is hydrogen, C₁₋₄ alkylor phenyl; and R₄ is hydrogen, C₁₋₉ alkyl, phenyl, phenyl C₁₋₄ alkyl,naphthyl, naphthyl C₁₋₄ alkyl, any of which phenyl or naphthyl moietiesmay be substituted by one or more halogen, trifluoromethyl, C₁₋₆ alkyl,C₁₋₆ alkoxy or nitro groups; except that when R₂ is hydrogen or C₁₋₄alkyl, R₄ must be other than hydrogen or C₁₋₉ alkyl; and salts thereof.

One particularly suitable sub-group of compounds within such compoundsof the formula (I) include those of the formula (II): ##STR6## wherein:m is as defined in formula (I);

p is 6 or 8;

X' is CO, CHOH or C(CH₃)OH;

R¹ ₁ is hydrogen or C₁₋₄ alkyl;

R¹ ₂ is hydrogen, methyl or ethyl; and

R¹ ₄ is a group of formula (III): ##STR7## wherein S is a bond, or aC₁₋₆ alkylene group which may be straight chain or branched by one ortwo methyl groups at the same or different carbon atoms; and W, Y and Zare each hydrogen or fluorine, chlorine or bromine atoms, or CF₃,methyl, ethyl, n- or iso-propyl, methoxy, ethoxy, n- or iso-propoxy ornitro groups; and salts thereof.

Often S will be a group --(CH₂)_(q) -- wherein q is 0 to 4.

In formula (II) m is most suitably 1, p is most suitably 6, X' is mostsuitably CO, and R¹ ₂ is most suitably methyl or ethyl. Also, W is mostsuitably hydrogen.

A second interesting sub-group of compounds within such compounds offormula (I) include those of formula (IV): ##STR8## wherein m, p, X', R¹₁ and R¹ ₂ are as defined in formula (II), and R² ₄ is a group offormula (V): ##STR9## wherein S, W, Y and Z are as defined in formula(III); and salts thereof.

Often S will be a group --(CH₂)_(q) -- wherein q is 0 to 4.

In formula (IV) m is most suitably 1, p is most suitably 6, X¹ is mostsuitably CO and R¹ ₂ is most suitably methyl or ethyl.

A third sub-group of compounds within such compounds of formula (I) ofparticular interest are those of formula (VI): ##STR10## wherein m, p,X¹ and R¹ ₁ are as defined in formula (II), and R³ ₄ is a group offormula (III), a group of formula (V) or a C₄₋₉ alkyl group; and saltsthereof.

The most suitable values for m and p in formula (VI) are 1 and 6respectively, and X¹ is most suitably CO.

When R³ ₄ is a C₄₋₉ alkyl group, suitable and preferred straight chainand branched groups R³ ₄ include those previously described as suitableand preferred for the group R₄ when R₄ is C₄₋₉ alkyl group. Suchpreferred groups R³ ₄ include straight chain pentyl, hexyl and heptyl,and of these normally the most useful is straight chain hexyl. Otherpreferred groups R¹ ₄ include CH(CH₃)R¹ ₅ and C(CH₃)₂ R¹ ₅ wherein R¹ ₅is straight chain butyl, pentyl or hexyl.

A forth sub-group of compounds that is within formula (I) is of formula(VII): ##STR11## wherein: p, m, X¹, R¹ ₁ and R¹ ₂ are as defined informula (II); and

R^(a) ₄ is a group of formula (VIII): ##STR12## wherein S is as definedin formula (III) and r is 0 to 3; and salts thereof.

Often S will be a group --(CH₂)_(q) -- wherein q is 0 to 6.

In formula (VII) we prefer that p is 6. Most suitably X¹ is CO, R¹ ₂ ismethyl or ethyl, and m is 1.

A fifth sub-group of compounds within formula (I) of interest is offormula (IX): ##STR13## wherein: p, m, X¹ and R¹ ₁ are as defined informula (II); R^(b) ₂ and R^(b) ₄ are separately C₅₋₉ alkyl, or groupsof formula (III), (V) or (VIII) as defined; or R^(b) ₂ and R^(b) ₄ takentogether with the carbon atom to which they are joined represent C₅₋₈cycloalkyl; and salts thereof.

In formula (IX) we prefer that p is 6. Most suitably X¹ is CO and m is1.

Compounds of the formula (II), (IV), (VI), (VII), or (IX) as defined,but wherein X¹ is a protected CO group, are also of particular utility.

The compounds of the formula (I) have asymmetric centres, and thus arecapable of existing in a number of stereoisomeric forms. The inventionextends to each of these stereoisomeric forms, and to mixtures thereof.The different stereoisomeric forms may be separated one from the otherby the usual methods.

The invention also provides a process for the preparation of thecompounds of the formula (I), which process comprises decarboxylating acompound of the formula (X): ##STR14## wherein m, n, R₁, R₂, R₃ and R₄are as defined in formula (I), to yield a compound of the formula (I)wherein X is CO; and thereafter if desired protecting X, or converting Xin the thus formed compound to CROH by reduction when R is hydrogen orby reaction with a C₁₋₄ alkyl Grignard reagent or C₁₋₄ alkyl metalliccomplex when R is C₁₋₄ alkyl, and then optionally protecting the CROHhydroxy moiety.

The decarboxylation reaction may be brought about under basic, acid orneutral conditions in conventional manner. For example when m=1 thereaction is conveniently effected by leaving the chosen compound of theformula (X) in an inert solvent, for example overnight.

After the reaction R₁ may be varied by conventional de-esterificationand/or esterification reactions. Similarly protected CROH and R₃ hydroxymoieties may be deprotected by conventional methods. For example, whenR₃ is a benzyloxy group, the benzyl group may readily be removed byhydrogenolysis. Thus it may be seen that `protected hydroxy` compoundsof the formula (I) are useful intermediates in the preparation of thecorresponding `free hydroxy` compounds of the formula (I).

The conversion of a compound of the formula (I) wherein X is CO to thecorresponding compound wherein X is protected CO may be carried outunder conventional reaction conditions for, for example, carbonyladdition and condensation reactions.

The conversion of a compound of the formula (I) wherein X is CO to thecorresponding compound wherein X is CHOH may be carried out byconventional methods for reducing a ketone to an alcohol, for example bysodium borohydride reduction.

The conversion of a compound of the formula (I) wherein X is CO to thecorresponding compound wherein X is CROH in which R is C₁₋₄ alkyl may becarried out by conventional Grignard or alkyl metal, (suitably alkyllithium) reactions.

When R₁ is hydrogen, salts of compounds of the formula (I) may beprepared in conventional manner, for example by reacting the chosencompound of the formula (I) with the required base.

It is frequently convenient however to generate the desired compound ofthe formula (I) directly from an ester of the formula (XI), and oftenthis will in fact be the preferred route: ##STR15## where CO₂ R₆ is aconventional ester group. In such a case R₆ is preferably a benzyl groupor a lower alkyl group such as ethyl or the like. Thus treatment of acompound of the formula (XI) with, for example, lithium iodide dihydrateand collidine in anydrous solvents brings about simultaneousde-esterification and decarboxylation. In cases where m=1, the compoundof formula (XI) can be de-esterified and decarboxylated by leaving thecompound standing in an inert solvent, e.g. overnight, or by heating thecompound alone or in a high boiling solvent such as toluene or xylene.

It will be appreciated that compounds of the formulae (X) and (XI) areuseful intermediates and as such form a useful aspect of this invention.

The compounds of formula (XI) may be prepared by the ring closure of thecorresponding diester of formula (XII): ##STR16## wherein m, n, R₁, R₂,R₃, and R₄ are as defined in formula (I), R₆ is as defined in formula(XI), and R₇ is a group such that CO₂ R₇ is an ester group.

In the process of the invention the group CO₂ R₁ in the intermediates offormula (X), (XI) and (XII) will normally represent an ester group, andif acids of the formula (I) (wherein R₁ is hydrogen) are required theywill be obtained by de-esterification of the corresponding compound ofthe formula (I) wherein CO₂ R₁ is an ester group. Usually the estergroup CO₂ R₇ in formula (XII) will be the same ester group as CO₂ R₁,and for the sake of convenience the ester group CO₂ R₆ will alsonormally be the same ester group as CO₂ R₁. The ester groups CO₂ R₁ /R₆/R₇ are suitably C₁₋₄ alkyl esters such as methyl and ethyl esters.

Generally, the ring closure takes place in a dry organic solvent using astrong base such as sodium hydride or sodium ethoxide (or other ⁻ OR₆ or⁻ OR₇ group) to bring about the initial proton abstraction from theα-methylene group.

It has been found that sodium ethoxide in benzene, or potassiumt-butoxide in toluene, benzene or hexamethyl-phosphoramide give goodresults.

Compounds of formula (XII) are novel useful intermediates and as such,from an aspect of this invention.

Compounds of formula (XII) may be prepared by the esterification of acorresponding acid or by the reaction of a compound of the formula(XIII): ##STR17## with a reactive acylating derivative of an acid of theformula

    HO.sub.2 C--(CH.sub.2).sub.m --CO.sub.2 H                  (XIV)

or an ester thereof.

Suitable reactive acylating derivatives include (a) compounds of theformula (XV):

    R.sub.6 O.sub.2 C--(CH.sub.2).sub.m --CO--Z                (XV)

where Z is a readily displaceable group such as Cl, Br, OSO₂ CH₃, OSO₂C₆ H₄ CH₃, OCO(CH₂)_(m) CO₂ R₆ or like, (b) compounds of the formula(XV) wherein Z is OH in the presence of dicyclohexyl carbodiimide as acondensing agent, and (c) a cyclic anhydride such as: ##STR18##

The reaction of the compound (XIII) with the compound (XIV) and (XV)occurs under conventional acylation conditions.

The novel substituted amino acids (XIII) are highly useful intermediatesand form an important aspect of the present invention.

The compounds (XIII) may be prepared by the reaction of an amine of theformula (XVI):

    H.sub.2 N--CH.sub.2 CH.sub.2 CR.sub.2 R.sub.3 R.sub.4      (XVI)

with a compound of the formula (XVII): ##STR19## where Q is a groupreadily displaceable by an electron rich group.

Suitable groups Q include I, Br, Cl, O.SO₂.CH₃, O.SO₂ C₆ H₄ CH₃ andother conventional groups.

The displacement reaction occurs under conventional reaction conditions,for example, in an alcoholic solvent in the presence of Na₂ CO₃ orpyridine.

When R₂ is hydrogen or lower alkyl then the amine (XVI) can be preparedby conventional methods. However when R₂ and R₄ are higher alkyl orcyclic groups as defined in formula (I), then the amine is best preparedby the following reaction scheme, or a scheme chemically analogousthereto: ##STR20##

Compounds within the formula (I) have useful pharmacological activity.For example compounds within the formula (I) have anti-gastric secretionactivity, cardiovascular activity e.g. anti-hypertensive activity,platelet aggregation inhibition activity, affect the respiratory tracte.g. bronchodilator activity, and have antifertility and smooth muscleactivity.

In general it may be said that compounds within the formula (I) have arange of pharmacological activities similar to those shown by thenatural prostaglandins, but that these activities tend to be rather moreselective.

The invention therefore also provides a pharmaceutical compositioncomprising a compound of the formula (I) and a pharmaceuticallyacceptable carrier.

Clearly the formulation of the said pharmaceutical composition willdepend on the nature of the activity shown by the chosen compound of theformula (I), and on other factors such as a preference in a particulararea of therapy for a particular mode of administration.

The compositions may be in the form of tablets, capsules, powders,granules, lozenges or liquid preparations, such as oral or sterileparenteral solutions or suspensions.

Tablets and capsules for oral administration may be in unit dosepresentation form, and may contain conventional excipients such asbinding agents; for example syrup, acacia, gelatin, sorbitol,tragacanth, or polyvinylpyrrolidone; filler, for example lactose, sugar,maize-starch, calcium phosphate, sorbitol or glycine; tablettinglubricants, for example magnesium stearate, talc, polyethylene glycol orsilica; disintegrants, for example potato starch; or acceptable wettingagents such as sodium lauryl sulphate. The tablets may be coatedaccording to methods well known in normal pharmaceutical practice. Oralliquid preparations may be in the form of, for example, aqueous or oilysuspensions, solutions, emulsions, syrups, or elixirs, or may bepresented as a dry product for reconstitution with water or othersuitable vehicle before use. Such liquid preparations may containconventional additives such as suspending agents, for example sorbitol,syrup, methyl cellulose, glucose syrup, gelatin, hydroxyethylcellulose,carboxymethyl cellulose, aluminium stearate gel or hydrogenated ediblefats, emulsifying agents, for example lecithin, sorbitan monooleate, oracacia; non-aqueous vehicles (which may include edible oils), forexample almond oil, fractionated coconut oil, oily esters such asglycerine, propylene glycol, or ethyl alcohol; preservatives, forexample methyl or propyl p-hydroxybenzoate or sorbic acid, and ifdesired conventional flavouring or colouring agents. The compounds ofthe formula (I) may also if desired be incorporated in a food-stuff, forexample in the form of a biscuit.

For parenteral administration, fluid unit dosage forms are preparedutilizing the compound of the formula (I) and a sterile vehicle. Thecompound, depending on the vehicle and concentration used, can be eithersuspended or dissolved in the vehicle. In preparing solutions thecompound can be dissolved for injection and filter sterilized beforefilling into a suitable vial or ampoule and sealing. Advantageously,adjuvants such as a local anesthetic, preservatives and buffering agentscan be dissolved in the vehicle. Parenteral suspensions are prepared insubstantially the same manner except that the compound is suspended inthe vehicle instead of being dissolved and sterilization cannot beaccomplished by filtration. The compound can be sterilized by exposureto ethylene oxide before suspending in the sterile vehicle.Advantageously, a surfactant or wetting agent is included in thecomposition to facilitate uniform distribution of the compound.

When appropriate, the compositions of this invention may be presentedfor aerosol or oral administration, or as a microfine powder forinsufflation.

As is common practice, the compositions will usually be accompanied bywritten or printed directions for use in the medical treatmentconcerned.

It has been found that a number of the compounds of the formula (I) arepotent inhibitors of gastric secretion, and thus have commercial utilityas anti-ulcer agents. In treatment of this nature, the compositioncontaining the formula (I) will preferably be formulated in a manner toallow oral administration. Normally 0.01 mg/kg to 500 mg/kg per day,most suitably 0.1 to 100 mg/kg per day, of the compound of the formula(I) in composition form will be administered in such treatment.

Also a number of compounds of the formula (I) have particularly usefulactivity on the respiratory tract, and thus find utility as for examplebronchodilators. Normally compositions containing such compounds of theformula (I) will be formulated for aerosol or oral administration, or asa microfine powder for insufflation, and the treatment will comprise theadministration of from 0.001 mg/kg to 100 mg/kg per day of the compoundin composition form.

Further, a number of compounds of the formula (I) are particularlypotent inhibitors of platelet aggregation, and thus compositionscontaining such compounds are useful inter alia for administration tohumans and animals to prevent clot formation for example after surgeryto prevent postoperative thrombosis: in geriatric patients to preventtransient cerebral ischemic attacks; and long-term prophylaxis followingmyocardial infarcts and strokes--and in general in the treatment orprophylaxis of any disorder caused by an over pronounced tendency ofblood platelets to aggregrate. Such compositions also have applicationsin the storage of whole blood in blood banks, and whole blood to be usedin heart-lung machines, or to be circulated through organs, e.g. heartand kidneys, which have been removed from a cadaver and prior totransplant.

It will of course be realised that the precise dosage used in thetreatment of any of the hereinbefore described disorders will depend onthe actual compound of the formula (I) used, and also on other factorssuch as the seriousness of the disorder being treated.

The invention also provides a method of treatment and/or propylaxis ofdisorders in human beings which comprises the administration of thesufferer of an effective amount of a compound of the formula (I).

It will be realised that when the compound of the formula (I) exhibitsplatelet aggregration inhibition activity then the invention alsoprovides a method of inhibiting such aggregration in vitro.

It will also be realised that when a compound of formula (I) exhibitsanti-fertility activity, then the invention also provides a method ofpreventing pregnancy comprising the administration to the person oranimal of an effective amount of the compound of the formula (I).

The following Examples illustrate the preparation of compounds of theformula (I) and their pharmacological properties.

EXAMPLE 1 N,N-Dibenzyl-2-aminoethyl methyl ketone

Freshly distilled methyl vinyl ketone (70.5 g) was added dropwise withstirring to a solution of dibenzylamine (197 g) in dry ethanol (50 ml)and the mixture was stirred for 30 minutes.

The solvent was evaporated and the solid residue washed with a smallamount of ethanol to give N,N-dibenzyl-2-aminoethyl methyl ketone as apale yellow solid (211.6 g, 79% yield), m.p. 58°-59°.

N,N-Dibenzyl-2-aminoethyl ethyl ketone was similarly prepared as ayellow oil from ethyl vinyl ketone and dibenzylamine.

I.R. spectrum--carbonyl absorption at 1700 cm⁻¹.

NMR spectrum--

10 proton singlet at 2.7τ[(C₆ H₅ CH₂)₂ N--]

4 proton broad multiplet at 7.3τ(>N-CH₂ CH₂ --)

3 proton triplet at 9.05τ, ##STR21##

EXAMPLE 2 3-Methyl-1-(N,N-dibenzylamino)-5-phenyl-pentan-3-ol

2-Phenylethyl magnesium bromide was prepared under nitrogen frommagnesium (8.04 g) and 2-bromoethyl benzene (54.8 g) in drytetrahydrofuran (100 ml).

A solution of N,N-dibenzyl-2-aminoethyl methyl ketone (50 g) in drytetrahydrofuran (200 ml) was added dropwise to the Grignard reagent. Themixture was stirred and refluxed overnight.

A saturated solution of ammonium chloride was added and the productextracted three times with ether. The organic fractions were combined,dried over magnesium sulphate and evaporated in vacuo to give3-methyl-1-(N,N-dibenzylamino)-5-phenyl-pentan-3-ol as a yellow oil(75.6 g).

I.R. spectrum--

broad OH absorption at 3330 cm⁻¹.

absence of carbonyl absorption.

The compounds shown in Table 1 were similarly prepared.

                  TABLE 1    ______________________________________     ##STR22##                                      OH                                      absorp-    Com-                              tion    pound Precursor      R.sub.4      (cm.sup.-1)    ______________________________________    1     Bromobenzene   C.sub.6 H.sub.5                                        3300    2     Benzyl bromide CH.sub.2 C.sub.6 H.sub.5                                        3300    3     1-Bromo-3-phenyl                         (CH.sub.2).sub.3 C.sub.6 H.sub.5                                        3300          propane    4     β-Bromo-isopropyl                         CH.sub.2 CH(CH.sub.3)C.sub.6 H.sub.5                                        3330          benzene    5     2-Bromoethyl-4"- fluorobenzene                          ##STR23##     3350    6     1 Bromo-3-(2'- methoxyphenyl)- propane                          ##STR24##     3350    ______________________________________

EXAMPLE 3 1-Amino-3-methyl-5-phenyl-pentan-3-ol

A solution of 3-methyl-1-(N,N-dibenzylamino)-5-phenyl-pentan-3-ol (75.5g) in ethanol (200 ml) was added to a slurry of 10% Pd/C (8 g) inethanol. The mixture was hydrogenated at 200 psi and 70° for three days.

The mixture was filtered through kieselguhr and evaporated. The oilyproduced was fractionally distilled to give1-amino-3-methyl-5-phenyl-pentan-3-ol as a colourless liquid (15.8 g,40% yield), b.p. 136°/0.3 mm Hg.

The compounds shown in Table 2 were similarly prepared.

                  TABLE 2    ______________________________________     ##STR25##                                       NH.sub.2, OH                                       absorption    Compound            R.sub.4        B.p.        (cm.sup.-1)    ______________________________________    7       C.sub.6 H.sub.5                           --          3300    8       CH.sub.2 C.sub.6 H.sub.5                           95-105°/0.6 mm                                       --    9       (CH.sub.2).sub.3 C.sub.6 H.sub.5                             130°/0.2 mm                                       --    10      CH.sub.2 CH(CH.sub.3)C.sub.6 H.sub.5                           --          3330    11             ##STR26##     --          3350    12             ##STR27##     --          3350    ______________________________________

EXAMPLE 4

Acetonitrile (7 g) in dry ether (30 ml) was added dropwise to asuspension of sodamide (9.97 g) in liquid ammonia (500 ml). The mixturewas stirred for 10 minutes, then a solution of phenylamyl-ketone (30 g)in dry ether (30 ml) was added dropwise. After stirring for anadditional hour solid ammonium chloride (14 g) was added. The ammoniawas evaporated and during the evaporation ether (50 ml) was added. Theresidue was treated with water (150 ml) and the ether layer wasseparated. The aqueous phase was extracted with ether and the combinedether phase was washed with brine until the washings were neutral, thenwas dried over magnesium sulphate and evaporated in vacuo to give ayellow oil. The unchanged starting materials were removed by vacuumdistillation, and the residue which solidified on standing, wasreasonably pure 3-hydroxy-3-phenyl-n-octanitrile (12.5 g).

I.R. spectrum--

CN absorption at 2250 cm⁻¹.

OH absorption at 3430 cm⁻¹.

1-Hydroxy-1-cyanomethyl-cyclohexane, b.p. 101°/0.1 mm was similarlyprepared.

EXAMPLE 5

3-Hydroxy-3-phenyl-n-octanitrile (12.45 g) in dry ether (50 ml) wasadded dropwise to a stirred suspension of lithium aluminum hydride (2.18g) in dry ether (300 ml). Reflux occurred and this was maintained byexternal heating for 45 minutes after the final addition. The mixturewas cooled (ice-bath) and water (2.5 ml), 15% NaOH solution (2.5 ml) andwater (7.5 ml) were added dropwise in sequence. The resulting mixturewas stirred for half-an-hour at room temperature, then was filteredthrough Kieselguhr. The resulting solution was dried over magnesiumsulphate, and evaporated in vacuo to give3-hydroxy-3-phenyl-n-octylamine (12.1 g, 97% crude yield).

I.R. spectrum--

strong absorption 3000-3500 cm⁻¹ due to OH, NH₂ absence of CNabsorption.

1-Hydroxy-1-(2'-aminoethyl)-cyclohexane, b.p. 81°/0.15 mm, was similarlyprepared.

EXAMPLE 6 Diethyl2-(N-3'-hydroxy-3'-methyl-5'-phenyl-n-pentyl)-aminoazelate

Diethyl 2-bromoazelate (9.7 g) in dry ethanol (50 ml) was added dropwiseto a refluxing solution of 1-amino-3-methyl-5-phenyl-pentan-3-ol (5 g)in dry ethanol (150 ml) containing a suspension of anhydrous sodiumcarbonate (2.7 g). The mixture was refluxed overnight.

The mixture was filtered and the filtrate evaporated in vacuo. Theresidue was taken up in ether and the ethereal solution was washed withwater until the washings were neutral, dried over magnesium sulphate andevaporated in vacuo to give diethyl2-(N-3'-hydroxy-3'-methyl-5'-phenyl-n-pentyl)-amino-azelate as a paleyellow oil (10.4 g).

I.R. spectrum--

broad OH, NH absorption at 3300 cm⁻¹.

ester carbonyl absorption at 1730 cm⁻¹.

The compounds shown in Table 3 were similarly prepared:

                  TABLE 3    ______________________________________     ##STR28##    Compound   R.sub.2     R.sub.4    ______________________________________    13         CH.sub.3    C.sub.6 H.sub.5    14         CH.sub.3    CH.sub.2 C.sub.6 H.sub.5    15         CH.sub.3    (CH.sub.2).sub.3 C.sub.6 H.sub.5    16         CH.sub.3    CH.sub.2 CH(CH.sub.3)C.sub.6 H.sub.5    17         CH.sub.3                            ##STR29##    18         CH.sub.3                            ##STR30##    19         C.sub.6 H.sub.5                           C.sub.5 H.sub.11    20                ##STR31##    ______________________________________

In each case, the I.R. spectrum showed a broad OH, NH absorption at 3300cm⁻¹ and an ester carbonyl absorption at 1730 cm⁻¹.

EXAMPLE 7 Diethyl2-[N-3'-hydroxy-3'-methyl-5'-phenyl-n-pentyl)-N-ethoxycarbonylacetyl]-aminoazelate

A solution of monoethyl malonate (2.9 g) in dry methylene chloride (50ml) was added to a solution of diethyl2-(N-3'-hydroxy-3'-methyl-5'-phenyl-n-pentyl)-aminoazelate (10.4 g) indry methylene chloride (50 ml). The mixture was stirred at roomtemperature and a solution of dicyclohexylcarbodiimide (5.0 g) in drymethylene chloride (25 ml) was added dropwise. Stirring was continuedovernight.

The mixture was filtered and the filtrate evaporated in vacuo. Theresidue was taken up in ether and the ethereal solution was washed withdilute hydrochloric acid, sodium bicarbonate solution and then withsodium chloride solution until the washings were neutral. The etherlayer was dried over magnesium sulphate and evaporated in vacuo to givediethyl2-[N-3'-hydroxy-3'-methyl-5'-phenyl-n-pentyl)-N-ethoxycarbonylacetyl]-aminoazelateas a yellow oil (11.9 g).

I.R. spectrum--

broad OH absorption at 3400 cm⁻¹.

carbonyl absorptions at 1730 cm⁻¹ and 1640 cm⁻¹.

The compounds shown in Table 4 were similarly prepared.

                  TABLE 4    ______________________________________     ##STR32##    Compound   R.sub.2      R.sub.4    ______________________________________    21         CH.sub.3     C.sub.6 H.sub.5    22         CH.sub.3     CH.sub.2 C.sub.6 H.sub.5    23         CH.sub.3     (CH.sub.2).sub.3 C.sub.6 H.sub.5    24         CH.sub.3     CH.sub.2 CH(CH.sub.3)C.sub.6 H.sub.5    25         CH.sub.3                             ##STR33##    26         CH.sub.3                             ##STR34##    27         C.sub.6 H.sub.5                            C.sub.5 H.sub.11    28                ##STR35##    ______________________________________

In each case, the I.R. spectrum showed a broad OH absorption at 3400cm⁻¹ together with carbonyl absorptions at 1730 cm⁻¹ and 1640 cm⁻¹.

EXAMPLE 82-(6'-Ethoxycarbonyl-n-hexyl)-1-(3"-hydroxy-3"-methyl-5"-phenyl-n-pentyl)-pyrrolidin-3,5-dione

Potassium tert-butoxide (2.18 g) was added in small portions over onehour to a warm solution of diethyl2-[N-(3'-hydroxy-3'-methyl-5'-phenyl-n-pentyl)-N-ethoxycarbonylacetyl]-aminoazelate(11.9 g) in dry toluene (100 ml). The mixture was gently refluxed for 2hours.

The solvent was evaporated in vacuo and the residue taken up in water.The solution was extracted twice with ether and the aqueous layer wasacidified with dilute hydrochloric acid and extracted with ether. Thisethereal solution was washed with brine and dried over magnesiumsulphate to give a solution of4-ethoxycarbonyl-2-(6'-ethoxycarbonyl-n-hexyl)-1-(3"-hydroxy-3"-methyl-5"-phenyl-n-pentyl)-pyrrolidin-3,5-dione.The product decarboxylated on standing in ether solution overnight. Thesolvent was evaporated in vacuo to give2-(6'-ethoxycarbonyl-n-hexyl)-1-(3"-hydroxy-3"-methyl-5"-phenyl-n-pentyl-pyrrolidin-3,5-dioneas a yellow oil (4.7 g).

I.R. spectrum--

broad OH absorption at 3430 cm⁻¹.

carbonyl absorptions at 1760 cm⁻¹, 1720 cm⁻¹ and 1680 cm⁻¹.

The compounds shown in Table 5 were similarly prepared.

                  TABLE 5    ______________________________________     ##STR36##                     I.R. spectrum                               OH      carbonyl    Com-                       absorption                                       absorptions    pound R.sub.2                 R.sub.4       cm.sup.-1                                       cm.sup.-1    ______________________________________    29    CH.sub.3                 C.sub.6 H.sub.5                               3400    1675, 1720, 1760    30    CH.sub.3                 CH.sub.2 C.sub.6 H.sub.5                               3400    1675, 1720, 1760    31    CH.sub.3                 (CH.sub.2).sub.3 C.sub.6 H.sub.5                               3400    1675, 1720, 1760    32    CH.sub.3                 CH.sub.2 CH(CH.sub.3)C.sub.6 H.sub.5                               3450    1680, 1720, 1760    33    CH.sub.3                  ##STR37##    3450    1680, 1725, 1765    34    CH.sub.3                  ##STR38##    3400    1680, 1720, 1760    35    C.sub.6 H.sub.5                 C.sub.5 H.sub.11                               3400    1675, 1725, 1760    36                  ##STR39##    3450    1680,1725, 1760    ______________________________________

EXAMPLE 92-(6'-Ethoxycarbonyl-n-hexyl)-3-hydroxy-1-(3"-hydroxy-3"-methyl-6"-phenyl-n-hexyl)-pyrrolidin-5-one

Sodium borohydride (290 mg) was added portionwise to a solution of2-(6'-ethoxycarbonyl-n-hexyl)-1-(3"-hydroxy-3"-methyl-6"-phenyl-n-hexyl)pyrrolidin-3,5-dione(2.5 g) in dry ethanol (50 ml). The mixture was stirred at roomtemperature for 2 hours.

The solvent was evaporated in vacuo and the residue was taken up inether. The ethereal solution was washed with very dilute hydrochloricacid and with water, dried over magnesium sulphate, and evaporated invacuo to give a colourless oil. The product was purified by columnchromatography to give2-(6'-ethoxycarbonyl-n-hexyl)-3-hydroxy-1-(3"-hydroxy-3"-methyl-6"-phenyl-n-hexyl)-pyrrolidin-5-oneas a colourless oil (1.5 g, 60% yield).

I.R. spectrum

broad OH absorption at 3400 cm⁻¹.

carbonyl absorptions at 1725 cm⁻¹ and 1665 cm⁻¹.

The compounds shown in Table 6 were similarly prepared.

                  TABLE 6    ______________________________________     ##STR40##                     I.R. Spectrum                                         carbonyl    Com-                       OH absorption                                         absorptions    pound R.sub.2                 R.sub.4       cm.sup.-1 cm.sup.-1    ______________________________________    37    CH.sub.3                 C.sub.6 H.sub.5                               3400      1670, 1720    38    CH.sub.3                 CH.sub.2 C.sub.6 H.sub.5                               3400      1670, 1720    39    CH.sub.3                 (CH.sub.2).sub.2 C.sub.6 H.sub.5                               3400      1670, 1720    40    CH.sub.3                  ##STR41##    3430      1670, 1725    41    CH.sub.3                  ##STR42##    3400      1665, 1725    ______________________________________

PHARMACOLOGICAL DATA Anti-secretory activity

The anti-secretory activity of the compounds was determined by theirinhibition of pentagastrin-stimulated gastric acid secretion in theperfused rat stomach preparation (Ghosh and Schild preparation).

2-(6'-Ethoxycarbonyl-n-hexyl)-1-(3"-hydroxy-3"-methyl-6"-phenyl-n-hexyl)-pyrrolidin-3,5-dioneinhibited acid secretion with an approximate ED₅₀ of 850 μg/kg,intravenously.

Inhibition of platelet aggregation

The compounds were examined for their ability to inhibit guinea pigplatelet aggregation induced, in vitro, by 5.45×10⁻⁷ M adenosinediphosphate.

2-(6'-Ethoxycarbonyl-n-hexyl)-1-(3"-hydroxy-3"-methyl-6"-phenyl-n-hexyl)pyrrolidin-3,5-dioneinhibited platelet aggregation with an IC₅₀ of 1.6×10⁻⁵ M.

Bronchodilation activity

The compounds were examined for their ability to inhibit5-hydroxytryptamine-induced bronchoconstriction in the anaesthetisedartificially respired guinea pig (Konzett-Rossler preparation).

2-(6'-Ethoxycarbonyl-n-hexyl)-1-(3"-hydroxy-3"-methyl-6"-phenyl-n-hexyl)-pyrrolidin-3,5-dioneinhibited bronchoconstriction with an IC₅₀ of 137 μg/kg, intravenously.

Antifertility activity

The antifertility activity of the compounds was determined by theirability to inhibit pregnancy in mated hamsters.

2-(6'-Ethoxycarbonyl-n-hexyl)-3-hydroxy-1-(3"-hydroxy-3"-methyl-5"-phenyl-n-pentyl)-pyrrolidin-5-onecompletely inhibited pregnancy in hamsters when dosed at 25 mg/kg,subcutaneously, on days 6, 7 and 8 after mating.

Toxicity

No apparent side effects were observed after administration of2-(6'-ethoxycarbonyl)-n-hexyl)-1-(3"-hydroxy-3"-methyl-6"-phenyl-n-hexyl)-pyrrolidin-3,5-dioneat 100 mg/kg subcutaneously in the hamster and I.D. in the rat.

What we claim is:
 1. A compound of the formula: ##STR43## or apharmaceutically acceptable salt thereof wherein n has a value of 4 to8;R₁ is hydrogen, alkyl of 1 to 12 carbon atoms, phenyl, benzyl ortoluyl; R₂ when taken independently of R₄ is hydrogen or alkyl of 1 to 4carbon atoms; and R₄ when taken independently of R₂ is ##STR44## inwhich q has a value of 0 to 6 andr has a value of 0 to 3; or R₂ and R₄,together with the carbon atom to which they are attached, arecycloalkylidene of 5 to 8 carbon atoms.
 2. A compound according to claim1 wherein n is
 6. 3. A compound according to claim 1 wherein R₂ ismethyl.
 4. A compound according to claim 1 wherein q is 0 to
 4. 5. Acompound according to claim 1 whereinn has a value of from 6 to 8; R₁ ishydrogen, methyl or ethyl; and R₂ is hydrogen or methyl.
 6. The methodof treating conditions in a human or other animal responsive to naturalprostaglandins which comprises administering thereto an effective amountof a compound according to claim
 1. 7. A pharmaceutical composition foreffecting a prostaglandin-like activity which comprises an effectiveamount of a compound according to claim 1 in combination with apharmaceutical carrier.